Topoisomerases are vital nuclear enzymes which function to resolve topological dilemmas in DNA, such as overwinding, underwinding and catenation, which normally arise during replication, transcription and perhaps other DNA processes. These enzymes allow DNA to relax by forming enzyme-bridged strand breaks that act as transient gates or pivotal points for the passage of other DNA strands. Topoisomerase-targeting drugs appear to interfere with this breakage-reunion reaction of DNA topoisomerases. In the presence of topoisomerase-active agents, an aborted reaction intermediate, termed a ‘cleavable complex’, accumulates and results in replication/transcription arrest, which ultimately leads to cell death. The development of topoisomerase I-active agents therefore offers a new approach to the multi-regimental arsenal of therapies currently used in the clinic for the treatment of cancer. An article in Cancer Chemother. Pharmacol [1994, 34 (suppl): S 41–S 45] discusses topoisomerase I-active compounds that are in clinical studies and these have been found to be effective clinical anti-tumor agents. Structurally these clinical candidates are related to the alkaloid camptothecin.
Indolo[2,3-a]carbazole alkaloids such as rebeccamycin (U.S. Pat. Nos. 4,487,925 and 4,552,842) and its water-soluble, clinically-active analog, 6-(2-diethylaminoethyl)rebeccamycin (U.S. Pat. No. 4,785,085), are useful antitumor agents which target DNA. Furthermore, fluoroindolocarbazoles (WO 98/07433) have been disclosed as antineoplastic agents with topoisomerase I inhibitory activity. Indolo[2,3-a]carbazole derivatives related to the Rebeccamycin class are disclosed (EP Appl. 0 545 195 B1 and U.S. Pat. No. 0,602,597 A2; Cancer Research 1993, 53, 490–494; ibid, 1995, 55, 1310–1315) and claimed to exhibit anti-tumor activity; however the major mechanism of action of these derivatives may not be like camptothecin, which acts as a topoisomerase I poison. Related indolocarbazoles are also disclosed (WO 95/30682) and claimed to exhibit anti-tumor activity. Hudkins, et al. have disclosed a series of fused pyrrolocarbazoles (WO 96/11933 and U.S. Pat. No. 5,475,110) and reported in vitro biological activity such as inhibition of neuronal choline acetyltransferase (ChAT) and protein kinase C (PKC) inhibition for some compounds. U.S. Pat. No. 5,468,849 discloses certain fluororebeccamycin analogs as useful antitumor agents, along with a process for their production by fluorotryptophan analog feeding of a rebeccamycin-producing strain of Saccharothrix aerocolonigenes, preferably Saccharothrix aerocolonigenes C38,383-RK2 (ATCC 39243). Glicksman, et al. disclose indolocarbazole alkaloids (U.S. Pat. No, 5,468,872), while Kojiri, et al. disclose indolopyrrolocarbazoles having a dissacharide substituent (WO 96/04293). Mazur and Hiller report the synthesis of simple 5-hydroxymethyl glycosides (J. Org. Chem. 1997, 62, 4471), while Danishefsky, et al. (J. Am. Chem. Soc. 1996, 118, 2825) describe the synthesis of 5-methoxy substituted sugar derivatives. Despite these reports, there remains the need for novel and potent cytotoxic compounds useful for inhibiting topoisomerase I activity.